Zinc (Zn) regulates numerous cellular functions. Zn deficiency is common in females; ~80% of women and 40% of adolescent girls consume inadequate Zn. Zn deficiency enhances oxidative stress, inflammation and DNA damage. Oxidative stress and inflammation is associated with breast disease. We hypothesized that Zn deficiency increases oxidative stress in the mammary gland, altering the microenvironment and architecture. Zn accumulated in the mammary glands of Zn deficient mice and this was associated with macrophage infiltration, enhanced oxidative stress and over-expression of estrogen receptor α. Ductal and stromal hypercellularity was associated with aberrant collagen deposition and disorganized e-cadherin. Importantly, these microenvironmental alterations were associated with substantial impairments in ductal expansion and mammary gland development. This is the first study to show that marginal Zn deficiency creates a toxic microenvironment in the mammary gland impairing breast development. These changes are consistent with hallmarks of potential increased risk for breast disease and cancer.

Breastfeeding can reduce breast cancer risk; however, unknown factors modify this protective effect. Zinc (Zn) modulates an array of cellular functions including oxidative stress, cell proliferation, motility and apoptosis. Marginal Zn intake is common in women and is associated with breast cancer. We reported that marginal Zn intake in mice leads to mammary gland hypoplasia and hallmarks of pre-neoplastic lesions. In the present study, we tested the hypothesis that marginal Zn intake confounds the protective effect of lactation on breast cancer. Nulliparous mice fed control (ZA, 30 mg Zn/kg) or a marginal Zn diet (ZD, 15 mg Zn/kg), were bred and offspring were weaned naturally. Post-involution, mice were gavaged with corn oil or 7,12-dimethylbenz(a)anthracene (DMBA, 1 mg/wk for 4 weeks) and tumor development was monitored. A ZD diet led to insufficient involution, increased fibrosis and oxidative stress. Following DMBA treatment, mice fed ZD had higher oxidative stress in mammary tissue that correlated with reduced levels of peroxiredoxin-1 and p53 and tended to have shorter tumor latency and greater incidence of non-palpable tumors. In summary, marginal Zn intake creates a toxic mammary gland microenvironment and abrogates the protective effect of lactation on carcinogenesis.

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Breast cancer is the most common cancer among women. While breastfeeding can reduce breast cancer risk, several studies found no protective effect. We showed that marginal zinc (Zn) intake compromises mammary gland (MG) expansion and function during lactation and is associated with hallmarks of pre‐neoplastic lesions such as collagen deposition, macrophage infiltration, and ductal hyperplasia in the MG of nulliparous mice. Herein, we hypothesized that marginal Zn deficiency abrogates the protective effect of breastfeeding on breast cancer risk. C57BL/6 mice were fed a Zn adequate (ZA; 30mg Zn/kg) or Zn deficient (ZD; 15mg Zn/ kg) diet. Mice were bred, and 2 wk post‐weaning were gavaged with 7,12‐dimethylbenzanthracene (DMBA; 1mg/0.1mL corn oil) or corn oil (control) weekly for 4 wk. Tumor progression was monitored for 24 wk. ZD mice had lower matrix metalloproteinase 2 activity (p<0.01) and insufficient involution, shorter tumor latency (p=0.05), and tended to have greater palpable (35% vs 12% p=0.137) and non‐palpable tumors (p=0.08). ZD mice had greater oxidative stress, e‐cadherin expression and collagen deposition in the MG. Moreover, mammary tumors in ZD mice accumulated Zn and had characteristics of a more invasive phenotype. Our results suggest that consuming inadequate dietary Zn may impair post‐ lactational regression and abrogate the protective effect of breastfeeding on breast cancer. Grant Funding Source: Intramural support, Departments of Surgery and Nutritional Sciences, Penn State University